Hemodialysis vascular access dysfunction is the single most important cause of hospitalization in hemodialysis patients and is responsible for a very significant morbidity within this patient population. Thrombosis of PTFE dialysis grafts due to venous stenosis as a result of venous neointimal hyperplasia (VNH), is the most common cause of vascular access dysfunction. Surprisingly, there are currently no effective therapeutic interventions for VNH despite its clinical importance. Analysis of cell types and cytokines in dialysis patients with venous stenosis due to VNH and data from a validated pig model of venous neointimal hyperplasia, that is very similar to the human lesion have been described. These studies clearly demonstrate that smooth muscle cell (SMC) proliferation and the formation of microvessels (endothelial cell proliferation), within the neointima and adventitia are critical features of VNH. In addition, it is likely that PTFE dialysis grafts are the ideal clinical model to test out novel local interventions, in view of their superficial location and easy accessibility. It is therefore proposed to test out novel locally delivered anti-proliferative therapies in a validated pig model of VNH, in the hope of being able to rapidly translate positive findings into a clinical setting of great need. Three local interventions will be evaluated in this proposal for their anti-proliferative effects. (a) External radiation therapy: Initial studies in the pig model, have demonstrated a reduction in VNH (albeit less than in models of coronary angioplasty), with a single dose of l6Gy. We now plan to optimize a radiation schedule for VNH by testing out 3 different radiation regimens (b) Local polymeric delivery of paclitaxel and TNP-470: A local polymeric delivery system comprising ethylene-vinyl-acetate matrices loaded with paclitaxel and TNP-470 (both are potent anti-proliferative agents) will be developed and tested in vitro against SMC and endothelial cells. Polymeric matrices will then be wrapped around the graft vein anastomosis in a perivascular configuration in an attempt to reduce luminal stenosis and VNH. (c) Combination radiation therapy and local anti-proliferative therapy: The most effective radiation and anti-proliferative regimens from (a) and (b) will be combined in this final analysis, in the hope of achieving a synergistic effect. We believe that the results from this study could transform the clinical care of hemodialysis patients and at the same time result in the successful clinical application of local therapy for the treatment of neointimal hyperplasia.